Characterization and manipulation of CD4+CD25+ T regulatory cells from normal and SIV-infected African green monkeys and Rhesus macaques

Abstract

CD4⁺CD25⁺ T regulatory cells (Tregs) are an essential cellular subtype of the immune system that suppress T-cell activation and proliferation and may hold the key to protection against numerous important human diseases. Non-human primates (NHPs) represent excellent animal models for human diseases, including AIDS. We determined the phenotype, cytokine production and function of Tregs in normal and SIV-infected rhesus macaques (RMs) and African green monkeys (AGMs). These two species infected with SIVmac and SIVagm respectively, differ in regard to their levels of T-cell immune activation and proliferation and, consequently, AIDS progression. Our study demonstrates that fully functional Tregs are present in both normal and SIV-infected RMs, and AGMs, showing a dose-dependent suppression of conventional CD4⁺ and CD8⁺ T-cell proliferation. Similar to humans and mice, simian Tregs express surface and intracellular markers, such as FoxP3, CTLA-4 and CD127. Our study shows that simian Tregs have the same phenotype and function as human CD4⁺CD25⁺FoxP3 ⁺ cells and therefore NHPs can be used to study the role of this T-cell subset in driving different pathogenic conditions. We also show that differences in the Tregs between the NHP pathogenic and natural SIV infections exist, and that these differences may be essential in triggering the diverse routes of progression to AIDS in RMs. In addition, we show that CD4⁺CD25 ⁺ T-cells can be induced from CD4⁺CD25neg T-cells by inducing expression of FoxP3 with TGFβ in both non-human primates (NHP) species tested. Induced RM Tregs conferred suppressive function of conventional CD4⁺ T-cell proliferation similar to naturally-derived CD4 ⁺CD25⁺ Tregs.